PI: Anderson, Deborah M Project Summary ?Development of a host targeted therapeutic for pneumonic plague? Project Summary Yersinia pestis is the causative agent of bubonic, pneumonic and septicemic plague, diseases that were responsible for three major pandemics, including the infamous black death that killed 250 million people in Europe in the Middle Ages. Although outbreaks of human plague are contained by effective public health measures, they occur each year due to the stable rodent-flea enzootic cycle of Y. pestis in areas throughout the world. Antibiotic prophylaxis has been effective in reducing person-to-person spread of plague, but the treatment of plague after symptoms develop has an unacceptably high rate of failure leading to nearly 30% mortality worldwide. Plague, especially the pneumonic and septicemic forms, is a devastating disease that progresses rapidly to severe bronchopneumonia and sepsis causing clinical collapse of the patient within days of exposure. Antibiotics are ineffective because the disease involves not only bacterial virulence but also multi- organ damage caused by the failed regulation of inflammation. In the proposed research, cobalt protoporphyrin IX will be used to stimulate the protective cellular response of heme oxygenase in order to provide tissue repair and anti-inflammatory signals that dampen host-induced tissue damage during pneumonic plague. The long term goals of this program are to develop a new treatment strategy for plague and other infectious diseases wherein systemic hyper-inflammatory responses can be reversed by heme oxygenase activation to improve outcome.